Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-970, Brazil.
Graduate Program in Biosciences and Technology of Bioactive Products, Institute of Biology, University of Campinas, Campinas 13083-862, Brazil.
Cells. 2019 Aug 17;8(8):921. doi: 10.3390/cells8080921.
To identify underlying mechanisms involved with metastasis formation in Wilms tumors (WTs), we performed comprehensive DNA methylation and gene expression analyses of matched normal kidney (NK), WT blastemal component, and metastatic tissues (MT) from patients treated under SIOP 2001 protocol. A linear Bayesian framework model identified 497 differentially methylated positions (DMPs) between groups that discriminated NK from WT, but MT samples were divided in two groups. Accordingly, methylation variance grouped NK and three MT samples tightly together and all WT with four MT samples that showed high variability. WT were hypomethylated compared to NK, and MT had a hypermethylated pattern compared to both groups. The methylation patterns were in agreement with methylases and demethylases expression. Methylation data pointed to the existence of two groups of metastases. While hierarchical clustering analysis based on the expression of all 2569 differentially expressed genes (DEGs) discriminated WT and MT from all NK samples, the hierarchical clustering based on the expression of 44 genes with a differentially methylated region (DMR) located in their promoter region revealed two groups: one containing all NKs and three MTs and one containing all WT and four MTs. Methylation changes might be controlling expression of genes associated with WT progression. The 44 genes are candidates to be further explored as a signature for metastasis formation in WT.
为了确定Wilms 瘤（WTs）转移形成所涉及的潜在机制，我们对符合 SIOP 2001 方案治疗的患者的匹配正常肾脏（NK）、WT 胚性成分和转移组织（MT）进行了全面的 DNA 甲基化和基因表达分析。线性贝叶斯框架模型确定了 497 个组间差异甲基化位置（DMPs），可区分 NK 和 WT，但 MT 样本分为两组。相应地，甲基化方差将 NK 和三个 MT 样本紧密地分组在一起，而所有 WT 与四个显示高变异性的 MT 样本分组在一起。WT 与 NK 相比呈低甲基化状态，而 MT 与两组相比呈高甲基化状态。甲基化模式与甲基转移酶和去甲基化酶的表达一致。甲基化数据表明存在两组转移。虽然基于 2569 个差异表达基因（DEGs）的所有表达进行的层次聚类分析将 WT 和 MT 与所有 NK 样本区分开来，但基于 44 个基因的表达进行的层次聚类，这些基因的启动子区域存在差异甲基化区域（DMR），则揭示了两组：一组包含所有 NK 和三个 MT，另一组包含所有 WT 和四个 MT。甲基化变化可能控制与 WT 进展相关的基因的表达。这 44 个基因是作为 WT 转移形成标志物进一步探索的候选基因。
